Non-invasive islet β-cell markers track with weight-loss interventions for type 2 diabetes: a prospective cohort study

Abstract Objective This study investigated the longitudinal impact of intensive medical intervention (IMI) and bariatric surgery procedures on indirect measures of pancreatic β-cell death and function. Methods Eighty-four participants (28 non-type 2 diabetes T2D, 56 T2D) from the HEADS UP study were assessed at baseline and 1-year post-intervention. Circulating unmethylated and methylated insulin gene INS DNA were quantified from blood samples via droplet digital polymerase chain reaction (PCR). Metabolic biomarkers, including fasting plasma glucose, HbA1c, proinsulin-to-insulin ratio, insulin, and C-peptide, were analyzed. Results At baseline, participants with T2D had significantly higher levels of unmethylated INS DNA and higher unmethylated-to-methylated INS DNA ratios than individuals without T2D. After 1-year, significant reductions in these biomarkers were observed primarily in the T2D group. Bariatric surgeries yielded greater improvements in metabolic profiles and reductions in unmethylated INS DNA than IMI. Despite substantial metabolic improvement, participants with T2D maintained elevated proinsulin-to-insulin ratios, indicating alterations to β-cell function. Conclusions Circulating unmethylated INS DNA is a non-invasive index of β-cell death and responds to weight-loss interventions. Metabolic surgeries are more effective than IMI in preserving β-cell mass and function, highlighting their potential in diabetes management. Long-term studies are necessary to confirm these initial findings.